Y gastric bypass (RYGB) is the most effective therapy for morbid obesity, but it has a ϳ20% failure rate. To test our hypothesis that outcome depends on differential modifications of several energy-related systems, we used our established RYGB model in Sprague-Dawley diet-induced obese (DIO) rats to determine mechanisms contributing to successful (RGYB-S) or failed (RYGB-F) RYGB. DIO rats were randomized to RYGB, sham-operated Obese, and sham-operated obese pair-fed linked to RYGB (PF) groups. Body weight (BW), caloric intake (CI), and fecal output (FO) were recorded daily for 90 days, food efficiency (FE) was calculated, and morphological changes were determined. D-Xylose and fat absorption were studied. Glucose-stimulated vagal efferent nerve firing rates of stomach were recorded. Gut, adipose, and thyroid hormones were measured in plasma. Mitochondrial respiratory complexes in skeletal muscle and expression of energy-related hypothalamic and fat peptides, receptors, and enzymes were quantified. A 25% failure rate occurred. RYGB-S, RYGB-F, and PF rats showed rapid BW decrease vs. Obese rats, followed by sustained BW loss in RYGB-S rats. RYGB-F and PF rats gradually increased BW. BW loss in RYGB-S rats is achieved not only by RYGB-induced decreased CI and increased FO, but also via sympathetic nervous system activation, driven by increased peptide YY, CRF, and orexin signaling, decreasing FE and energy storage, demonstrated by reduced fat mass associated with the upregulation of mitochondrial uncoupling protein-2 in fat. These events override the compensatory response to the drop in leptin levels aimed at conserving energy. food efficiency; gut and adipose hormones; mitochondria; obesity BARIATRIC OPERATIONS are currently the only treatment for morbid obesity (defined as a body mass index of 39 or greater or weight at least 50% above normal). Of the 180,000 -200,000 bariatric operations performed in 2006, ϳ80% were Roux-en-Y gastric bypass (RYGB). RYGB also reverses and ameliorates the major cardiovascular and metabolic risk factors, including Type 2 diabetes mellitus and hyper-and dyslipidemia (12, 72), reduces the long-term mortality and morbidity associated with obesity, and decreases health care costs (15).Despite the success of the RYGB operation, 20% of patients "fail to maintain long-term weight loss." Non-surgically related failure usually occurs within the first three postoperative years (12), suggesting a metabolic-endocrine compensatory etiologic mechanism.Weight loss induced by RYGB occurs biphasically. Initially there is rapid weight loss lasting 1-3 yr, followed by prolonged weight stabilization (39). Both occur despite a gradual increase in caloric intake during the same period (72). Our RYGB model in diet-induced obese Sprague-Dawley rats (52) also shows a postoperative biphasic weight change pattern. In this model, ϳ10 -13 rat days is equivalent to 1 human year (62), thus allowing us to follow rats postoperatively for a considerably long time compared with human subjects.Conventional surgical b...